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G A Yanus, T A Akhapkina, A O Ivantsov, E V Preobrazhenskaya, S N Aleksakhina, I V Bizin, A P Sokolenko, N V Mitiushkina, E Sh Kuligina, E N Suspitsin, A R Venina, M M Holmatov, O A Zaitseva, O S Yatsuk, D V Pashkov, A M Belyaev, A V Togo, E N Imyanitov, A G Iyevleva
Distribution of cancer-predisposing mutations demonstrates significant interethnic variations. This study aimed to evaluate patterns of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies. APC gene defects were identified in 26/38 (68%) subjects with colon polyposis; 8/26 (31%) APC mutations were associated with 2 known mutational hotspots (p.E1309Dfs*4 [n = 5] and p.Q1062fs* [n = 3]), while 6/26 (23%) mutations were novel (p.K73Nfs*6, p.S254Hfs*12, p.S1072Kfs*9, p.E1547Kfs*11, p...
February 6, 2018: Clinical Genetics
Mev Dominguez-Valentin, D Gareth R Evans, Sigve Nakken, Hélène Tubeuf, Daniel Vodak, Per Olaf Ekstrøm, Anke M Nissen, Monika Morak, Elke Holinski-Feder, Alexandra Martins, Pål Møller, Eivind Hovig
Background: In kindreds carrying path_BRCA1/2 variants, some women in these families will develop cancer despite testing negative for the family's pathogenic variant. These families may have additional genetic variants, which not only may increase the susceptibility of the families' path_BRCA1/2, but also be capable of causing cancer in the absence of the path_BRCA1/2 variants. We aimed to identify novel genetic variants in prospectively detected breast cancer (BC) or gynecological cancer cases tested negative for their families' pathogenic BRCA1/2 variant (path_BRCA1 or path_BRCA2)...
2018: Hereditary Cancer in Clinical Practice
Michele Ciavarella, Sara Miccoli, Anna Prossomariti, Tommaso Pippucci, Elena Bonora, Francesco Buscherini, Flavia Palombo, Roberta Zuntini, Tiziana Balbi, Claudio Ceccarelli, Franco Bazzoli, Luigi Ricciardiello, Daniela Turchetti, Giulia Piazzi
Germline variants in the APC gene cause familial adenomatous polyposis. Inherited variants in MutYH, POLE, POLD1, NTHL1, and MSH3 genes and somatic APC mosaicism have been reported as alternative causes of polyposis. However, ~30-50% of cases of polyposis remain genetically unsolved. Thus, the aim of this study was to investigate the genetic causes of unexplained adenomatous polyposis. Eight sporadic cases with >20 adenomatous polyps by 35 years of age or >50 adenomatous polyps by 55 years of age, and no causative germline variants in APC and/or MutYH, were enrolled from a cohort of 56 subjects with adenomatous colorectal polyposis...
January 24, 2018: European Journal of Human Genetics: EJHG
Misato Takao, Tatsuro Yamaguchi, Hidetaka Eguchi, Yuhki Tada, Masakazu Kohda, Koichi Koizumi, Shin-Ichiro Horiguchi, Yasushi Okazaki, Hideyuki Ishida
BACKGROUND: The base excision repair gene MUTYH is the causative gene of colorectal polyposis syndrome, which is an autosomal recessive disorder associated with a high risk of colorectal cancer. Since few studies have investigated the genotype-phenotype association in Japanese patients with MUTYH variants, the aim of this study was to clarify the clinicopathological findings in Japanese patients with MUTYH gene variants who were detected by screening causative genes associated with hereditary colorectal polyposis...
January 12, 2018: International Journal of Clinical Oncology
Preechaya Tajai, Bogdan I Fedeles, Tawit Suriyo, Panida Navasumrit, Jantamas Kanitwithayanun, John M Essigmann, Jutamaad Satayavivad
Paraquat (1,1'-dimethyl, 4,4'-bipyridinium dichloride; PQ), a widely used herbicide, is toxic to mammals through ingestion, inhalation and skin contact. Epidemiological data suggest that PQ is also mutagenic and carcinogenic, especially in high doses. The toxic and mutagenic properties of PQ are attributed to the ability of the molecule to redox-cycle, which generates reactive oxygen species (ROS) and subsequent oxidative stress. ROS also cause oxidative DNA damage such as 8-oxoguanine (8OG), a mutagenic base that, when replicated, causes G to T transversion mutations...
December 28, 2017: Free Radical Biology & Medicine
Jenny Nyqvist, Fredrik Persson, Toshima Z Parris, Khalil Helou, Elisabeth Kenne Sarenmalm, Zakaria Einbeigi, Åke Borg, Per Karlsson, Anikó Kovács
The number of patients with multiple primary malignancies has been increasing steadily in recent years. In the present study, we describe a unique case of an 81-year-old woman with 5 metachronous and synchronous primary malignant neoplasms. The patient was first diagnosed with an endometrium adenocarcinoma in 1997 and a colon adenocarcinoma in 2002. Eleven years after her colon surgery, in 2013, the patient presented with 3 other primary malignancies within a 4-month time span: an invasive malignant melanoma on the lower leg, an invasive mucinous breast carcinoma in the right breast, and a pleomorphic spindle cell sarcoma on the left upper arm...
September 2017: Case Reports in Oncology
Frank G J Kallenberg, Andrew Latchford, Nikki C Lips, Cora M Aalfs, Barbara A J Bastiaansen, Susan K Clark, Evelien Dekker
BACKGROUND: Patients with genetic adenomatous polyposis syndromes have an increased risk for duodenal cancer, and clear surveillance recommendations exist for this group. However, limited data are available on the duodenal phenotype of patients with multiple colorectal adenomas (10-99) without a germline APC or MUTYH mutation. OBJECTIVE: We aimed to assess the frequency, extent, and progression of duodenal adenomas in patients with multiple colorectal adenomas without a germline APC or MUTYH mutation...
January 2018: Diseases of the Colon and Rectum
Amrita Singh, Navneet Singh, Digambar Behera, Siddharth Sharma
Genes OGG1 and MUTYH are the two primary genes in Base excision repair pathway. OGG1 hydrolyzes the sugar phosphate backbone and remove the damaged base creating abasic site. MUTYH complements OGG1 as it particularly remove adenine mispaired with 8-oxo-G. Both OGG1 and MUTYH act as a check for the mis-incorporation of bases may be due to damages incurred on DNA. DNA isolation for 326 lung cancer cases and 330 controls was followed by genotyping making use of PCR-RFLP. Logistic regression was done to analyze the risk towards lung cancer...
December 5, 2017: Pathology Oncology Research: POR
Shengliang He, Jing Du, Fangqi Liu
Familial adenomatous polyposis (FAP) is one of the most common hereditary colorectal cancers. Its intestinal and extra-intestinal manifestations are correlated with mutation sties of the APC gene. Potential gene modulation sites in patients who have typical clinical manifestations but with unidentified APC mutations are also discussed, which included MUTYH gene, AXIN gene and certain epigenetic changes. With the generalization of Precision Medicine, to offer individualized treatment and surveillance strategy based on the genotype-phenotype correlation will be of great value for FAP patients...
December 10, 2017: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
Huiying Ma, Lodewijk A A Brosens, G Johan A Offerhaus, Francis M Giardiello, Wendy W J de Leng, Elizabeth A Montgomery
Colorectal cancer (CRC) accounts for over 8% of all deaths annually worldwide. Between 2 and 5% of all CRCs occur due to inherited syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis and Cowden/PTEN hamartoma syndrome. In addition, serrated polyposis is a clinically defined condition characterised by multiple colorectal serrated polyps and an increased risk of CRC but the genetics are not known. In most hereditary CRC syndromes, polyps undergo carcinogenesis, but the exact route to carcinoma seems to differ between the conditions...
January 2018: Pathology
Abdelghani Mazouzi, Federica Battistini, Sarah C Moser, Joana Ferreira da Silva, Marc Wiedner, Michel Owusu, Charles-Hugues Lardeau, Anna Ringler, Beatrix Weil, Jürgen Neesen, Modesto Orozco, Stefan Kubicek, Joanna I Loizou
DNA lesions caused by UV damage are thought to be repaired solely by the nucleotide excision repair (NER) pathway in human cells. Patients carrying mutations within genes functioning in this pathway display a range of pathologies, including an increased susceptibility to cancer, premature aging, and neurological defects. There are currently no curative therapies available. Here we performed a high-throughput chemical screen for agents that could alleviate the cellular sensitivity of NER-deficient cells to UV-induced DNA damage...
November 16, 2017: Molecular Cell
Micaella Kantor, Javier Sobrado, Sima Patel, Sara Eiseler, Christopher Ochner
MAP (MUTYH-associated polyposis) is a syndrome, described in 2002, which is associated with colorectal adenomas, with enhanced colorectal carcinogenesis. This review synthesizes the available literature on MAP and outlines its pathogenesis, association with colorectal tumorigenesis, screening, treatment, and the subtle differences between it and its close cousins-FAP and AFAP. The preponderance of data is collected using MAP guidelines. However, although AFAP and MAP appear similar, potentially important distinctions exist, warranting targeted diagnostic criteria and treatment approaches...
2017: Gastroenterology Research and Practice
Elena M Stoffel, Erika Koeppe, Jessica Everett, Peter Ulintz, Mark Kiel, Jenae Osborne, Linford Williams, Kristen Hanson, Stephen B Gruber, Laura S Rozek
BACKGROUND & AIMS: The incidence of colorectal cancer (CRC) in individuals younger than 50 years old is increasing. We sought to ascertain the proportion of young CRC cases associated with genetic predisposition. METHODS: We performed a retrospective study of individuals diagnosed with CRC at an age younger than 50 years, evaluated by the clinical genetics service at a single tertiary care cancer center from 1998 through 2015. We collected data on patient histories, tumor phenotypes, and results of germline DNA sequencing...
November 12, 2017: Gastroenterology
Robbert D A Weren, Marjolijn J L Ligtenberg, Ad Geurts van Kessel, Richarda M De Voer, Nicoline Hoogerbrugge, Roland P Kuiper
It is well-established now that germline genomic aberrations can underlie high-penetrant familial polyposis and colorectal cancer syndromes, but a genetic cause has not yet been found for the major proportion of patients with polyposis. Since next generation sequencing has become widely accessible, several novel, but rare, high-penetrant risk factors for adenomatous polyposis have been identified, all operating in pathways responsible for genomic maintenance and DNA repair. One of these is the base excision repair (BER) pathway...
November 3, 2017: Journal of Pathology
E Y Scott, K D Woolard, C J Finno, M C T Penedo, J D Murray
Cerebellar Abiotrophy (CA) is a neurodegenerative disease in Arabian horses affecting the cerebellum, more specifically the Purkinje neurons. Although CA occurs in several domestic species, CA in Arabian horses is unique in that a single nucleotide polymorphism (SNP) has been associated with the disease. Total RNA sequencing (RNA-seq) was performed on CA-affected horses to address the molecular mechanism underlying the disease. This research expands upon the RNA-seq work by measuring the impact of the CA-associated SNP on the candidate gene MutY homolog (MUTYH) and its regulation, isoform-specific expression and protein localization...
January 1, 2018: Brain Research
Kazuya Shinmura, Hisami Kato, Masanori Goto, Hong Tao, Yusuke Inoue, Satoki Nakamura, Haruki Yoshida, Emi Tsuzaki, Haruhiko Sugimura
To date, the types of mutations caused by 8-bromoguanine (8BrG), a major base lesion induced by reactive brominating species during inflammation, in human cells and the 8BrG repair system remain largely unknown. In this study, we performed a supF forward mutation assay using a shuttle vector plasmid containing a single 8BrG in three kinds of human cell lines and revealed that 8BrG in DNA predominantly induces a G → T mutation but can also induce G → C, G → A, and delG mutations in human cells...
2017: Oxidative Medicine and Cellular Longevity
Wenjing Jian, Kang Shao, Qi Qin, Xiaohong Wang, Shufen Song, Xianming Wang
Background: Breast cancer develops as a result of multiple gene mutations in combination with environmental risk factors. Causative variants in genes such as BRCA1 and/or BRCA2 have been shown to account for hereditary nature of certain breast cancers. However,other genes, such as ATM, PALB2, BRIP1, CHEK, BARD1, while lower in frequency, may also increase breast cancer risk. There are few studies examining the role of these causative variants. Our study aimed to examine the clinical and genetic characterization of hereditary breast cancer in a Chinese population...
2017: Hereditary Cancer in Clinical Practice
Guang Hua Li, Shinya Akatsuka, Shan Hwu Chew, Li Jiang, Takahiro Nishiyama, Akihiko Sakamoto, Takashi Takahashi, Mitsuru Futakuchi, Hiromu Suzuki, Kunihiko Sakumi, Yusaku Nakabeppu, Shinya Toyokuni
Oxidative stress including iron excess has been associated with carcinogenesis. The level of 8-oxoguanine, a major oxidatively modified base in DNA, is maintained very low by three distinct enzymes, encoded by OGG1, MUTYH and MTH1. Germline biallelic inactivation of MUTYH represents a familial cancer syndrome called MUTYH-associated polyposis. Here, we used Mutyh-deficient mice to evaluate renal carcinogenesis induced by ferric nitrilotriacetate (Fe-NTA). Although the C57BL/6 background is cancer-resistant, a repeated intraperitoneal administration of Fe-NTA induced a high incidence of renal cell carcinoma (RCC; 26...
October 13, 2017: Pathology International
Isabelle Sourrouille, Jérémie H Lefèvre, Conor Shields, Chrystelle Colas, Jerôme Bellanger, Benoît Desaint, Francois Paye, Emmanuel Tiret, Yann Parc
BACKGROUND: Duodenal polyposis is a manifestation of adenomatous polyposis that predisposes to duodenal or ampullary adenocarcinoma. Duodenal polyposis is monitored by upper GI endoscopies and may require iterative resections and prophylactic radical surgical treatment when malignancy is threatening. OBJECTIVE: The purpose of this study was to evaluate severity scoring for surveillance and treatment in a large series of duodenal polyposis. DESIGN: From 1982 to 2014, every patient surveyed by upper GI endoscopies for duodenal polyposis was included...
November 2017: Diseases of the Colon and Rectum
Enni Markkanen
Oxidative DNA damage constitutes a major threat to genetic integrity, and has thus been implicated in the pathogenesis of a wide variety of diseases, including cancer and neurodegeneration. 7,8-dihydro-8oxo-deoxyGuanine (8-oxo-G) is one of the best characterised oxidative DNA lesions, and it can give rise to point mutations due to its miscoding potential that instructs most DNA polymerases (Pols) to preferentially insert Adenine (A) opposite 8-oxo-G instead of the correct Cytosine (C). If uncorrected, A:8-oxo-G mispairs can give rise to C:G→A:T transversion mutations...
November 2017: DNA Repair
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